Discovery of Potent and Fast-Acting Antimalarial Bis-1,2,4-triazines.

Novel 3,3'-disubstituted-5,5'-bi(1,2,4-triazine) compounds with potent activity against parasites were recently discovered. To improve the pharmacokinetic properties of the triazine derivatives, a new structure-activity relationship (SAR) investigation was initiated with a focus on enhancing the metabolic stability of lead compounds. These efforts led to the identification of second-generation highly potent antimalarial bis-triazines, exemplified by triazine , which exhibited significantly improved metabolic stability (8 and 42 μL/min/mg protein in human and mouse liver microsomes).

3,3'-Disubstituted 5,5'-Bi(1,2,4-triazine) Derivatives with Potent in Vitro and in Vivo Antimalarial Activity.

A series of 3,3'-disubstituted 5,5'-bi(1,2,4-triazine) derivatives was synthesized and screened against the erythrocytic stage of Plasmodium falciparum 3D7 line. The most potent dimer, 6k, with an IC (50% inhibitory concentration) of 0.008 μM, had high in vitro potency against P.